This is a request for a MCSDA. The overall aim of the proposal is to provide the candidate with a supervised research and educational experience that will enable him to become an independent investigator in the clinical neurobiology of antipanic pharmacotherapies. The long-term goal of the candidate is to understand the relationship between therapeutic mechanisms of action of pharmacotherapy and the pathophysiology of panic and related anxiety disorders. The candidate is a junior faculty member at Yale University with substantial clinical, teaching and administrative responsibilities. A K08 award would permit him to fully dedicate himself to obtaining the experience and skills necessary to become an independent scientist. The research environment at Yale is ideal for career development in this field. The preceptors for the MCSDA, Dr. Dennis Charney, and Dr. Scott Woods, are active anxiety researchers with records of successful mentorship of clinical scientists. Two studies are proposed investigating the interaction between the serotonin (5-HT) system and two other transmitter systems implicated in the pathophysiology of PD, the norepinephrine (NE) and cholecystokinin/peptide (CCK) systems, in relation to the SRI treatment of PD. The specific aim of the first study is to test the hypothesis that the ability of the SRIs to suppress yohimbine-induced anxiety in PD patients is dependent on the availability of 5-HT. PD patients that have a panic attack in response to the challenge with the alpha2 adrenergic antagonist yohimbine but no panic following a saline control, will be stabilized on the SRI, fluvoxamine. Patients that respond to fluvoxamine will then participate in two experimental tests, one involving a tryptophan (TRP) depletion-yohimbine test, and another involving a control depletion-yohimbine test. If the hypothesis is correct, TRP depletion will impair the ability of fluvoxamine to suppress yohimbine-induced anxiety. The specific aim of the second study is to test the hypothesis that the ability of SRI therapy of PD to blunt the response to stimulation of the CCK system is dependent on the availability of 5-HT. PD patients that have a panic attack following challenge with the CCKb agonist, pentagastrin, but no panic after a saline control, will be treated with the SRI, fluvoxamine. Fluvoxamine responders will then participate in two experimental tests; a TRP depletion-pentagastrin test and then a control depletion-pentagastrin test. If the hypothesis is correct, TRP depletion will impair the ability of fluvoxamine to blunt pentagastrin-induced panic. The aims of the career development plan include the attainment of a sophisticated knowledge base about the preclinical mechanisms of SRIs by attendance of seminars and extramural site visits, acquisition of advanced and preclinical knowledge about the NE and CCK systems and expertise in the utilization of clinical neurobiologic paradigms that evaluate NE and CCK/ peptide function by seminar attendance and an extramural site visit, and acquisition of an advanced level of knowledge and skills pertaining to clinical research design and statistics by formal coursework.